Periventricular diffusivity reflects APOE ε4–modulated amyloid accumulation and cognitive impairment in the Alzheimer's disease continuum

INTRODUCTION Altered glymphatic‐related fluid dynamics are increasingly recognized as a feature of Alzheimer's disease (AD). We generalized an established diffusion imaging framework to quantify periventricular diffusivity (PVeD), hypothesizing that fast diffusion signals in the periventricular region can reflect amyloid beta (Aβ) deposition across the AD continuum. METHODS Participants from two multi‐site cohorts ( n = 440 and 414), comprising cognitively unimpaired individuals, those with mild cognitive impairment, and patients with AD, were included. We tested and validated the association of PVeD with Aβ burden and core AD characteristics. RESULTS Lower PVeD was extensively associated with greater Aβ burden, neurodegeneration, cognitive impairment, and clinical severity in the clinical cohort. Importantly, the relationship between PVeD and Aβ burden was significantly modulated by apolipoprotein E ( APOE ) ε4 status; APOE ε4 carriers exhibited a replicable stronger negative association. Baseline PVeD also predicted longitudinal cognitive decline. DISCUSSION These findings suggest that periventricular diffusion signals reflect APOE ε4–modulated Aβ burden and cognitive decline in AD. Highlights An automated method for quantifying periventricular diffusivity (PVeD) is developed. Lower PVeD is associated with higher amyloid load only in a mild cognitive impairment–dominant cohort. Higher amyloid burden may mediate the link between lower PVeD and poorer cognitive outcomes in the clinical cohort. Apolipoprotein E ε4 carriers show a reproducibly stronger inverse PVeD—amyloid association than non‐carriers. Baseline PVeD can predict longitudinal Mini‐Mental State Examination decline in two independent cohorts.